Lawrence Brody, Ph.D. Fong et al., NEJM , 361:123-134, 2009 Breast - - PowerPoint PPT Presentation

Lawrence Brody, Ph.D.

An Introduction to Genomics: Breast cancer genes, risk assessment and screening

Fong et al., NEJM, 361:123-134, 2009

Breast Cancer Genes

 What are they?  How do we find them?  What is their function?  How can they be used to improve health?

Change in the US Death Rates by Cause, 1950 & 2002

* Age-adjusted to 2000 US standard population. Sources: 1950 Mortality Data - CDC/NCHS, NVSS, Mortality Revised. 2002 Mortality Data–NVSR-Death Final Data 2001–Volume 52, No. 3.

Heart Diseases Cerebrovascular Diseases Pneumonia/ Influenza Cancer

1950 2002

Rate Per 100,000

http://www.cdc.gov/nchs/data/nvsr/nvsr52/nvsr52_03.pdf

Breast Cancer - USA

 207,090 new cases  39,840 deaths per year – lifetime risk of diagnosis ~ 12% (1/8) – risk of death from breast cancer - 3.4% (1/35)

ACS estimates for 2010

Cancer Death Rates: US Women, 1930-2001

Age-adjusted to the 2000 US standard population. Source: US Mortality Public Use Data Tapes 1960-2000, US Mortality Volumes 1930-1959, National Center for Health Statistics, Centers for Disease Control and Prevention, 2003.

Lung

Uterus

Breast

Ovary

Rate Per 100,000

Cancer Incidence: US Women, 1978-2008

SEER Data

Why Genetics?

• Prevention
• Early Detection
• Prognosis
• Tailored Therapy

Individuals: may inherit genetic variants that

lead to an increase in cancer risk.

Cells: acquire mutations associated with growth

advantage and/or escape from normal controls.

Somatic mutations

“cancer is a genetic disease”

Inherited variation

TUMOR SUPRESSOR GENES

Mutation Carriers Tumor Cell

Family History and Cancer Risk

In small percentage of families cancer appears to be inherited as a mendelian trait. 3-8% of breast cancer

Topography of Cancer Risk

Relative Risk

Minor Allele Frequency (%)

Relative Risk

Minor Allele Frequency (%)

10.0 2.0 1.0 0.1 1.0 10.0 30.0 1.5

Adapted from Foulkes WD NEJM, 359:2143, 2008

Topography of Cancer Risk

Sporadic Cancer

Inherited Cancer

Breast Cancer - Age at Dx

seer.nci.gov

BRCA1

Breast Cancer Gene One

BRCA2

BRCA1 and BRCA2 Families

Breast ~ 8X Prostate 2-3X Breast Ovarian 20-30X

Relative Risk

Minor Allele Frequency (%)

10.0 2.0 1.0 0.1 1.0 10.0 30.0 1.5

Adapted from Foulkes WD NEJM, 359:2143, 2008

Breast Cancer Genes

BRCA2 BRCA1 TP53

BRCA1 Mutations and Polymorphisms

1 kb

188del11bp Q1313ter G1541ter P1637L A1708E M1775R C64G 1294del40 E1250ter 3875del4 R1443ter R1443G 5085del19 5382insC 185delAG C61G 710C/T 1133insA Q356R E693N 2201C/T 2430T/C V772A R841W P871L E1038G 3233 A/G S1040N K1183R 4056C/T R1347G 4427C/T S1613G 5024C/T V1713A 5398del20 5438insC 1323delG K583E 3599del 11bp 5256delG 926ins11 1128insA 1201del11 Q562ter 2080insA 2294delG 2414delAG T826K 2477delC 2800delA 2863delTC 2982del5 3121delA 3166ins5 R1203ter 3884del1 4184del4 Y1853ter 2311 D694N

12/94

BRCA1 & BRCA2

The World’s most sequenced genes.

BRCA1 – BIC Database

BRCA1 and BRCA2 Founder Mutations

1/40 1/170 1/333 Icelanders Dutch

German, Swedish, Polish, Spanish, Cypriot, Afrikaner, Malaysian

Ashkenazi Jews

BRCA1 Mutation Data

Total Entries Distinct Alterations One Family Only Missense 2734 489 259 Nonsense 1046 176 84 Frameshift 4780 513 303 Splicing 598 175 100

BRCA1 Mutation Data

Missense 2734 489 259

The Unclassified Variant Problem

Breast Cancer Genes

• high penetrance / low frequency
• low penetrance / high prevalence

BRCA1, BRCA2

low relative risk, high attributable risk Association Studies!

CHEK2 - 1100delC

Controls 10,860 0.7%

Carriers

n

p= 0.0000001

OR= 2.34 CI 1.72-3.20

AJHG 74, 2004

Breast cancer 9,065 1.9%

Relative Risk

Minor Allele Frequency (%)

10.0 2.0 1.0 0.1 1.0 10.0 30.0 1.5

Adapted from Foulkes WD NEJM, 359:2143, 2008

Breast Cancer Genes

BRCA2 BRCA1 TP53 ATM BRIP1 CHEK2 PALB2

Genome Wide Association Study

Nature 447:1087-109, 28 June 2007

147 Institutional Affiliations

Relative Risk

Minor Allele Frequency (%)

10.0 2.0 1.0 0.1 1.0 10.0 30.0 1.5

Adapted from Foulkes WD NEJM, 359:2143, 2008

Breast Cancer Genes

BRCA2 BRCA1 TP53

ATM BRIP1 CHEK2 PALB2

MAP3KI

8q TOX3 6q CASP8 LSP1 FGFR2

Topography of Cancer Risk

Why Genetics?

• Prevention
• Early Detection
• Prognosis
• Tailored Therapy

Relative Risk

Minor Allele Frequency (%)

10.0 2.0 1.0 0.1 1.0 10.0 30.0 1.5

Adapted from Foulkes WD NEJM, 359:2143, 2008

Breast Cancer Genes

BRCA2 BRCA1 TP53

ATM BRIP1 CHEK2 PALB2

MAP3KI

8q TOX3 6q CASP8 LSP1 FGFR2

Inherited Cancer

BRCA1/ BRCA2 Mutation Associated Risk

Study Type Cancer by Age 70 Family-based 80-90% Population-based 30-50% Community-based 50-70% Proband-based 75-85%

Low penetrance / High prevalence

 Clinical Significance?

–Individual health –Public health

Genotype Driven Screening

Proportion of Cases Explained (%)

100 80 60 40 20 20 40 60 80 100

Proportion of the Population

Adapted from Pharoah PD NEJM 358, 2008

Distribution of Genetic Risk in the Population

Pharoah P et al. N Engl J Med 2008;358:2796-2803

Pharoah PD NEJM 358, 2008

Genotype Driven Screening

Proportion of Cases Explained (%)

100 80 60 40 20 20 40 60 80 100

Proportion of the Population

Adapted from Pharoah PD NEJM 358, 2008

Why Genetics?

• Prevention
• Early Detection
• Prognosis
• Tailored Therapy

BRCA1 & BRCA2

are DNA repair proteins

Anders C K et al. Clin Cancer Res 2010;16:4702-4710

PARP1 inhibitors kill established tumors

Audeh et al., Lancet, 6 July 2010

O’Shaughnessy Jan 2011

• vol. 364

NEJM

Tutt et al., Lancet, 6 July 2010

Why Genetics?

• Understand Mechanism
• Refine Characterization

Why Genetics?

• Prevention
• Early Detection
• Prognosis
• Tailored Therapy

Last slide

Mutation Database (BIC) BRCA1 11,672 BRCA2 11,171

Breast Cancer Genes - GWAS Genes

Risk Allele Freq Relative Risk Pop. Attributable Risk CASP8 0.86 1.13 20% FGFR2 0.38 1.26 19% TNRC9 0.25 1.20 10% “2q” 0.58 1.20 7% Gene

Adapted from Pharoah P et al. N Engl J Med 2008;358:2796-2803

Farmer et al., Nature, 434: 917, 2005 Bryant et al., Nature, 434: 913, 2005

Tailored therapy?